The Organic Chemistry of Drug Synthesis VOLUME 2 DANIEL LEDNICER Mead Johnson and Company Evansville, Indiana LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas A WILEY-INTERSCIENCE PUBLICATION JOHN WILEY AND SONS, New York • Chichester • Brisbane • Toronto Copyright © 1980 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging in Publication Data: Lednicer, Daniel, 1929- The organic chemistry of drug synthesis. "A Wiley-lnterscience publication." 1. Chemistry, Medical and pharmaceutical. 2. Drugs. 3. Chemistry, Organic. I. Mitscher, Lester A., joint author. II. Title. RS421 .L423 615M 91 76-28387 ISBN 0-471-04392-3 Printed in the United States of America 10 987654321 It is our pleasure again to dedicate a book to our helpmeets: Beryle and Betty. "Has it ever occurred to you that medicinal chemists are just like compulsive gamblers: the next compound will be the real winner." R. L. Clark at the 16th National Medicinal Chemistry Symposium, June, 1978. vii Preface The reception accorded "Organic Chemistry of Drug Synthesis11 seems to us to indicate widespread interest in the organic chemistry involved in the search for new pharmaceutical agents. We are only too aware of the fact that the book deals with a limited segment of the field; the earlier volume cannot be considered either comprehensive or completely up to date. Because the earlier book did, however, lay the groundwork for many of the structural classes or organic compounds that have proven useful in the clinic, it forms a natural base for a series that will, in fact, be comprehensive and up to date. This second volume fills some of the gaps left by the earlier work and describes developments in the field up to the end of 1976. More specifically, we have included literature and patent preparations for IX those compounds granted a USAN* generic name prior to and including 1976 that did not appear in Volume I. In assembling the first volume, we faced an apparently staggering mass of material. It seemed at the time that attempts to be inclusive would lead to an undigestible compendium. In order to keep the reader's interest, we chose instead to be selective about material to be included. Specifically, the first volume deals predominantly with organic compounds actually used in the clinic. It is, of course, well known that many compounds die in various stages of clinical trials, either from lack of effect, lack of superiority over existing drugs, or the presence of disqualifying side effects. Particularly since 1962, sponsoring companies have become much more demanding in the standards to be met by a drug before undertaking the cost involved in the clinical work leading to an NDA. For that reason, this period has seen a large increase in the number of compounds that have been granted generic names but have failed to achieve clinical use. Many such failed analogues were omitted from the previous volume. Since we now intend to make the series comprehensive, and since those analogues do have heuristic value, we have chosen to violate chronology and include them in the present volume. Volume 2 thus goes beyond simple updating. * United States Adopted Name New Drug Application x The organization of the material by chemical classes used earlier has been retained since it provided a convenient method for lending coherence to the subject matter. However, changes in emphasis of research in medicinal chemistry have led us to change the organization of the individual chapters. The small amount of new work devoted to some structural types (e.g., phenothiazines) that formed large units in the earlier book failed to provide sufficient material to constitute a chapter here; what material was available has simply been included under some broader new heading. As was the case previously, syntheses have been taken back to commonly available starting materials as far as possible. An exception to this rule will be found in the section on steroids. Many of the compounds described are corticoids, that are the products of intricate multistep syntheses. In the earlier volume, we described the preparation of some quite highly elaborated corticoids using plant sterols as start- ing materials. Many of these corticoids are used for preparation of compounds in this volume. Since there seems little point in simply reiterating those sections, a starting material is judged to be readily available if its preparation is described in the first volume. The reference will be to that book rather than to the original literature. We have endeavored, too, to approach biological activity in the same fashion as we did earlier. The first time some therapeutic indication occurs will be the occasion for a concise simplified discussion xi of the disease state and the rationale for the specific method of drug therapy. Biological activities are noted for each generic compound at the same time as its preparation. It will be emphasized again that the activities quoted are those given by the authors; this book is not intended as a critical text in pharmacology. "Organic Chemistry of Drug Synthesis, Volume 2" is addressed to the same audience as was Volume 1: graduate students in medicinal and organic chemistry, as well as practitioners in the two fields. This book also assumes that the reader will have a good understanding of synthetic organic chemistry and at least a rudimentary knowledge of biology. Finally, we express our sincere appreciation to several individuals who contributed time and talent to this project. Ms. Carolyn Kelly patiently typed the many versions of the manuscript, including the final camera-ready copy, in the midst of the press of her daily responsibilities. Sheila Newland drew the structural formulae, and John Swayze read the entire manuscript and made several useful suggestions to help clarify the text and reduce the number of typos. Ken McCracken and Peggy Williams were extremely helpful in guiding us through the intricacies of the IBM "Office System 6". Daniel Lednicer Evansville, Indiana Lester A. Mitscher Lawrence, Kansas January, 1980 xii Contents Chapter 1. Monocyclic and Acyclic Aliphatic Compounds 1 1. Cyclopentanes 1 a. Prostaglandins 1 b. Other Cyclopentanoids 7 2. Cyclohexanes 8 a. Cyclohexane and Cyclohexene Carboxylic Acids 8 b• Cyclohexylamines 12 c. Miscellaneous 17 3. Adamantanes 18 4. Noncyclic Aliphatics 20 References 23 Chapter 2. Derivatives of Benzyl and Benzhydryl Alcohols and Amines 26 1, Derivatives of Benzylamine 27 2. Benzhydrylamine Derivatives 30 3. Benzhydrol Derivatives 31 References 34 Xlll Chapter 3. Phenylethyl and Phenylpropylamines 36 1. Phenylethyl and Phenyl- propyl amines 36 a. Those With a Free ArOH Group 36 b. Those Agents With an Acylated or Alkylated ArOH Group 44 2. l-Phenyl-2-Aminopropanediols 45 3. Phenylethylamines 47 4. Phenylpropylamines 55 References 59 Chapter 4. Arylalkanoic Acids and Their Derivatives 63 1. Antiinflammatory Arylacetic Acids 63 2. Diaryl and Arylalkyl Acetic Acids: Anticholinergic Agents 71 3. Miscellaneous Arylalkanoic Acids 78 References 82 Chapter 5. Monocyclic Aromatic Compounds 85 1. Derivatives of Benzoic Acid 85 a. Acids 85 b. Anthranilic Acid and Derivatives 88 c. Amides 92 2. Derivatives of Aniline 95 3. Derivatives of Phenol 98 a. Basic Ethers 98 b. Phenoxyacetic Acids 101 c. Ethers of 1-Aminopropane- 2,3-diol 105 4. Arylsulfones and Sulfonamides 111 a. Sulfones 111 b. Sulfonamides 112 5. Functionalized Benzene Derivatives 119 a. Alkyl Analogues 119 b. Miscellaneous Derivatives 126 References 127 xiv Chapter 6. Steroids 135 1. Estranes 136 2. Androstanes 153 3. Pregnanes 164 a. 11-Desoxy Derivatives 164 b. 11-Oxygenated Pregnanes 176 References 200 Chapter 7. Polycyclic Aromatic and Hydro- aromatic Compounds 207 1. Indanes and Indenes 208 2. Naphthalenes 211 3. Fluorenes 217 4• Anthracenes 219 5. Dibenzocycloheptanes and Dibenzycycloheptenes 221 6. Tetracyclines 226 References 228 Chapter 8. Five-Membered Heterocycles 232 1. Derivatives of Pyrrole 233 2. Derivatives of Furan 238 3. Derivatives of Imidazole 242 4. Derivatives of Pyrazole 261 5. Derivatives of Oxazole and Isoxazole 262 6. Derivatives of Thiazole 267 7. Miscellaneous Five-Membered Heterocycles 270 References 273 Chapter 9, Six-Membered Heterocycles 278 1. Pyridines 278 2. Piperidines 284 3. Piperazines and Pyrazines 298 4. Pyrimidines 302 5. Miscellaneous Structures 304 References 308 Chapter 10. Morphinoids 314 1. Compounds Derived from Morphine 315 2. Morphinans 323 3. Benzomorphans 325 xv 4• Phenylpiperidines 328 References 337 Chapter 11. Five-Membered Heterocycles Fused to One Benzene Ring 340 1. Indoles 340 2• Reduced Indoles 348 3. Indazoles 350 4. Benzimidazoles 352 5. Miscellaneous 354 References 358 Chapter 12, Six-Membered Heterocycles Fused to One Benzene Ring 361 1. Quinolines 362 2. Isoquinolines 373 3• Quinazolines 379 4. Cinnolines and Quinoxalines 387 5. Miscellaneous Benzohetero- cycles 390 References 396 Chapter 13. Benzodiazepines 401 References 407 Chapter 14. Heterocycles Fused to Two Benzene Rings 409 1. Central Rings Containing One Heteroatom 410 2• Benzoheterocycloheptadienes 420 3. Derivatives of Dibenzolactams 424 4. Other Dibenzoheterocycles 430 References 432 Chapter 15, p-Lactam Antibiotics 435 1. Penicillins 437 2. Cephalosporins 439 3. Cephamycins 442 References 443 Chapter 16, Miscellaneous Fused Heterocycles 445 1. Compounds with Two Fused Rings 446 2. Compounds with Three or More Fused Rings 451 xvi 3. Punnes and Related Hetero- cycles 463 4. Polyaza Fused Heterocycles 469 5. Ergolines 475 References 480 Indexes 483 Cross Index of Drugs 485 Index 501 Errata for VOLUME 1 of ORGANIC CHEMISTRY OF DRUG SYNTHESIS 513 xvii Monocyclic and Acyclic Aliphatic Compounds 1.